The innate and adaptive immune systems
Our immune system is broadly divided into two separate “arms” that communicate with each other to protect us from infections. These two factions are termed the innate and adaptive immune systems1. The innate immune system is evolutionarily more ancient than its adaptive counterpart. It acts as a broad first-line of defense when we get infected with pathogens (think viruses, bacteria, and fungi)1. For example, a particular innate immune cell, termed a macrophage, can “eat” whole bacteria when it encounters them1.If the innate immune system is unable to clear the infection, it coordinates with the adaptive immune system to recruit reinforcements. Adaptive immunity (T and B cells) is more specialized than its innate counterpart, and therefore can mount highly specific responses, such as antibody production, against particular structures present on a given pathogen1. Due to their highly specific nature, adaptive immune responses are often sufficient to clear an infection. Even after an infection is cleared, a small portion of pathogen-specific B and T cells remain in our bodies as memory cells to protect us from another infection1.
What is immune memory?
Now what happens when we encounter the same infection again? Say we were vaccinated against tuberculosis with the BCG (or “Bacille Calmette-Guerin”) vaccine, then how would our immune system respond when we potentially encounter the causative bacteria of tuberculosis? Scientists previously thought that only the memory B and T cells will “remember” the 1st infection and will protect us when we get infected again1. This is the principle behind how vaccines work; we have been mildly “infected” during a tuberculosis vaccination, and when we encounter the Mycobacterium tuberculosis bacterium later in our life, the memory B and T cells respond against it quickly, thereby protecting us from getting sick.
However, over the past years, scientists have learned that innate immune cells (remember the 1st line defenders?) can also remember previous infections2. If you are surprised at this, you are not alone – scientists were too! This new discovery of memory by innate immune cells has been coined trained immunity and has received a lot of interest by scientists over the past few years2. Importantly, in certain situations, innate immune memory may be even “better” than memory by adaptive immune cells, due to its ability to protect us from a wider array of infections. This is especially true for the BCG vaccine, whose ability to reduce infant mortality worldwide cannot be explained solely by its tuberculosis-specific protective effects.
How does trained immunity work?
Although innate immune cells can remember previous foreign agents, the way they protect us during subsequent infections is fundamentally different than the protection provided by adaptive immune cells. For example, particular components on bacterial or fungal cell walls can “reprogram” innate immune cells to broadly protect us against different bacterial, fungal or even viral infections3! In fact, recent experiments have shown that immunization with the tuberculosis vaccine, BCG, may be able to protect humans against Yellow Fever Virus4.
How do innate immune cells become “reprogrammed” during an initial infection to mount protection against subsequent infections? This is a complicated question with an even more complicated answer that will take us on a journey into cellular epigenetics and metabolism3. Do not worry – I will try to replace those horrid flashbacks of high school exams involving these terms with more positive imagery.
Epigenetics: The “nurture” part of nature vs. nurture. All living beings have a “nature” encoded into every cell of their organism in the form of DNA. Various environmental stimuli can control a cell’s ability to read DNA and are thereby able to turn genes, which encode cellular components, “on” or “off”. This is achieved through modifying DNA around these genes to alter their accessibility by cellular machinery, which rely on reading this genetic code to synthesize proteins5. These DNA modifications in response to environmental stimuli are called epigenetic modifications5. Innate immune training relies on such epigenetic modifications or colloquially, “reprogramming”3. For example, BCG vaccination induces broad-scale epigenetic changes in innate immune cells, which causes them to secrete greater levels of protective proteins, or cytokines, upon subsequent challenge with viral, fungal, or bacterial agents3.
What then causes epigenetic changes in innate immune cells following primary challenge? It turns out that cellular metabolism – the pathways that serve to provide a cell with sufficient energy for survival and growth – can cause some of these changes. Recently, intermediate molecules in various metabolic pathways, termed metabolites, have received a lot of attention for their regulation of immune cell functionality. Indeed, specific metabolites can induce epigenetic reprogramming in innate immune cells that allow for their memory formation during infection3. For example, when innate immune cells are “trained” by exposure to a fungal cell wall component, they switch from a more energy-efficient form of metabolism, oxidative phosphorylation, to glycolysis, which is not as energetically favorable3. Why would they do this? 1) Glycolysis allows a cell to have more “building blocks” to make the necessary proteins for immune defense and expansion, and 2) the metabolites produced by glycolysis can act in concert with specific proteins that enable the epigenetic modifications required for innate immune training3. To put it more simply, during a 1st infection, the cells of our innate immune system switch their metabolism toward construction of defense proteins and epigenetic reprogramming, for improved efficacy during a 2nd infection3.
It turns out that mitochondria are primary drivers of the metabolic changes innate immune cells undergo during training. During innate immune training by bacterial or fungal cell wall components, there is a repurposing of the citric acid (TCA) cycle within mitochondria3. The TCA cycle is an important source of NADH, which are energy storage molecules that can later be used by the mitochondrial electron transport chain (ETC) to produce ATP, the main source of energy for the cell. As a factory that pumps out ATP, mitochondria are often, and aptly, termed the “powerhouse of the cell”. In addition to ATP through the TCA cycle, mitochondria are also paramount in providing other key metabolites for cell function and growth. One of these TCA intermediates, fumarate, drives epigenetic reprogramming of innate immune cells to fuel production of inflammatory defense molecules3, highlighting mitochondria as an important player in trained immunity.
As it turns out, the adage “the mitochondria are the powerhouse of the cell” might be an understatement for our innate immune system.
1. Charles A Janeway, J., Travers, P., Walport, M. & Shlomchik, M. J. Principles of innate and adaptive immunity. in Immunobiology: The Immune System in Health and Disease. 5th edition (Garland Science, 2001).
2. Netea, M. G. et al. Trained immunity: a program of innate immune memory in health and disease. Science 352, aaf1098 (2016).
3. Bekkering, S., Domínguez-Andrés, J., Joosten, L. A. B., Riksen, N. P. & Netea, M. G. Trained Immunity: Reprogramming Innate Immunity in Health and Disease. Annu. Rev. Immunol. 39, 667–693 (2021).
4. Arts, R. J. W. et al. BCG Vaccination Protects against Experimental Viral Infection in Humans through the Induction of Cytokines Associated with Trained Immunity. Cell Host Microbe 23, 89-100.e5 (2018).
5. What is Epigenetics? | CDC. Centers for Disease Control and Prevention https://www.cdc.gov/genomics/disease/epigenetics.htm (2022).